Self-Immolative Carbamate Linkers for CD19-Budesonide Antibody-Drug Conjugates

Bioconjug Chem. 2023 Oct 18;34(10):1835-1850. doi: 10.1021/acs.bioconjchem.3c00354. Epub 2023 Oct 3.

Abstract

Antibody-drug conjugates consist of potent small-molecule payloads linked to a targeting antibody. Payloads must possess a viable functional group by which a linker for conjugation can be attached. Linker-attachment options remain limited for the connection to payloads via hydroxyl groups. A releasing group based on 2-aminopyridine was developed to enable stable attachment of para-aminobenzyl carbamate (PABC) linkers to the C21-hydroxyl group of budesonide, a glucocorticoid receptor agonist. Payload release involves a cascade of two self-immolative events that are initiated by the protease-mediated cleavage of the dipeptide-PABC bond. Budesonide release rates were determined for a series of payload-linker intermediates in buffered solution at pH 7.4 and 5.4, leading to the identification of 2-aminopyridine as the preferred releasing group. Addition of a poly(ethylene glycol) group improved linker hydrophilicity, thereby providing CD19-budesonide ADCs with suitable properties. ADC23 demonstrated targeted delivery of budesonide to CD19-expressing cells and inhibited B-cell activation in mice.

MeSH terms

  • Animals
  • Budesonide
  • Carbamates / chemistry
  • Immunoconjugates* / chemistry
  • Mice

Substances

  • Immunoconjugates
  • alpha-aminopyridine
  • Carbamates
  • Budesonide
  • 4-azidobenzylcarazolol